title: Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model.
abstract: BACKGROUND
  Combinatorial interactions of transcription factors with cis-regulatory elements control the dynamic progression through successive cellular states and thus underpin all metazoan development. The construction of network models of cis-regulatory elements, therefore, has the potential to generate fundamental insights into cellular fate and differentiation. Haematopoiesis has long served as a model system to study mammalian differentiation, yet modelling based on experimentally informed cis-regulatory interactions has so far been restricted to pairs of interacting factors. Here, we have generated a Boolean network model based on detailed cis-regulatory functional data connecting 11 haematopoietic stem/progenitor cell (HSPC) regulator genes.
  
  
  RESULTS
  Despite its apparent simplicity, the model exhibits surprisingly complex behaviour that we charted using strongly connected components and shortest-path analysis in its Boolean state space. This analysis of our model predicts that HSPCs display heterogeneous expression patterns and possess many intermediate states that can act as 'stepping stones' for the HSPC to achieve a final differentiated state. Importantly, an external perturbation or 'trigger' is required to exit the stem cell state, with distinct triggers characterizing maturation into the various different lineages. By focusing on intermediate states occurring during erythrocyte differentiation, from our model we predicted a novel negative regulation of Fli1 by Gata1, which we confirmed experimentally thus validating our model. In conclusion, we demonstrate that an advanced mammalian regulatory network model based on experimentally validated cis-regulatory interactions has allowed us to make novel, experimentally testable hypotheses about transcriptional mechanisms that control differentiation of mammalian stem cells.
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: IBIVU Centre for Integrative Bioinformatics, VU University Amsterdam, AIMMS Amsterdam Institute for Molecules Medicines and Systems, VU University Amsterdam, De Boelelaan 1081, NKI-AVL The Netherlands.
authors.forename: Nicola
authors.initials: N
authors.lastname: Bonzanni
authors.forename: Abhishek
authors.initials: A
authors.lastname: Garg
authors.forename: K Anton
authors.initials: KA
authors.lastname: Feenstra
authors.forename: Judith
authors.initials: J
authors.lastname: Schütte
authors.forename: Sarah
authors.initials: S
authors.lastname: Kinston
authors.forename: Diego
authors.initials: D
authors.lastname: Miranda-Saavedra
authors.forename: Jaap
authors.initials: J
authors.lastname: Heringa
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
mesh_terms: D000818:Animals; D002460:Cell Line; D004912:Erythrocytes / Q000166:cytology; D053263:Gene Regulatory Networks; D005809:Genes, Regulator; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors